N-dialkylaminoalkyl-n-cycloalkylcycloalkylalkanamides



Patented Feb. 23, 1954 N-DIALKYLAMINOALKYL -Y- CYCLOAYLHYL-CYCLOALKYLALKANAMIDE S John W. Cusic, Skokie, Ill., assignor to G. D.Searle & 00., Chicago, 111., a corporation of Illinois No Drawing.Application July 23, 1952, Serial No. 300,509

13 Claims.

The present invention relates to a group of new organic compounds and inparticular to the N dialkylaminoalkyl N cycloalkyl cycloalkylalkanamidesof the structural formula represent bivalent saturated. aliphatichydrocarbon radicals such as ethylene, propylene, butylene, amylene,hexylene and polymethylene radicals such as trimethylene, tetramethyleneand octamethylene. While the radical A can also be a methylen radical,the radical B must contain at least two carbon atoms separating the twonitrogen atoms attached thereto. The lower alkyl radicals of thedialkylamino group can be methyl. ethyl. propyl, butyl, amyl and hexyl,wherein the propyl, butyl, amyl and hexyl groups may be of the straightchained or branch chained type. Valuable compounds are also obtainedwhere the radical N(lower allrylh is replaced by heterocyclic groupssuch as N-piperidino, N-lucetidine, N pyrrolidino, N-morpholino, N'alkyl- N-piperatino and like radicals.

The organic bases of the foregoing type form salts which are non-toxicin therapeutic dosage with a variety of inorganic and. strong organicacids including sulfuric, phosphoric, hydrochloric, hydrobromic,sulfamic, citric, oxalic, ascorbic and related acids. They also formquaternary ammonium salts with a variety of organic esters of sulfuric,hydrohalic and arematic acids. Among such esters are methyl chloride andbromide, ethyl chloride, propyl chloride.

butyl chloride. isobutyl chloride, benzyl chloride and bromide.phenethyl bromide, naphthylmethyl chloride, dimethyl sulfate. diethylsulfate, methyl henaenesulfonate. ethyl toluenesulfonate, ethylenechlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromideand crotyl bromide. By this quaternization procedure valuable glionblocking depressor agents are obtained. The object of this invention isto provide new chemical substances of thetype indicated above.

The invention also provides valuable medicinal substances. Thus thebases described and their acid addition salts are Valuable as diureticsand spasmolytics. These compounds also show valuable cardiovascular and,particularly, blood pressure reducing activity.

The following examples illustrative in detail certain of the compoundswhich comprise this invention and methods for producing same. Thisinvention is not to be construed as limited thereby in spirit or in.scope. It will be apparent to those skilled in the art that manymodifications in materials methods may be made without departing fromthe invention. In each of these examples temperatures are given indegrees centigrade 0.), relative amounts of materials in parts by weightand pressures during vacuum distillations in millimeters (mm) ofmercury.

This application is a continuation-in-part of applicants copendingapplication, Serial No. 167,266, filed June 9, 1950, now abandoned.

EXAMPLE 1 N c-dzethylaminoethyl) -N-cyclohea:yl-

a-cyclohexylacetamide A solution of parts of cyclohexylacetyl chlorideand 198 parts of N-diethylaminoethylhexahydroaniline in 2600 parts ofbenzene is heated at reflux temperature for 5 hours. The reactionmixture is extracted with dilute hydrochloric acid, the extract madealkaline by addition of dilute sodium hydroxide and the base is isolatedby ether extraction and evaporation of the solvent. The N-(fi-diethylaminoethyl) -Ncyclohexyl-acyclohexylacetainide distills atabout -192" C. at 2 mm. pressure. Treatment of an ether solution of thebase with a 25% solution of hydrogen chloride in isopropanol yields thehydrochloride which melts at about 1434M C. upon recrystallization fromethyl acetate. It has the structural formula EXAMPLE 2N,N-d2'isopropyl-N- (3-ethylcyclopentyl) -N' (3-methylcyclopentylacetylputrescz'ne -Diisopropylaminobutyronitrile is prepared by heatingdiisopropylamine with 7-0111010- butyronitrile for 39 hours in thepresence of some potassium iodide, extracting with ether and distillingat 25 mm. pressure and 118-120" C. 120 parts of the nitrile are thenstirred with 1200 4 parts of absolute ethanol and slowly treated with2600 parts of benzene is heated at reflux tom- 8 to 10 parts of sodium.The mixture is satuperature for hours. The reaction mixture is ratedwith dry hydrochloric acid, filtered and then extracted with dilutehydrochloric acid. fractionated in vacuo. The residue is treated Theextract is then made alkaline and the base with 50% sodium hydroxide,extracted with bena extracted with ether. This ether extract is driedzene, dried and distilled at 25 mm. pressure and over anhydrouspotassium carbonate, filtered, and about 108-110 C. 350 parts of theresulting evaporated. The N-(a-di'methylaminobutyb-N-N,N-diisopropylputrescine in 250 parts of ethacyclopentyl--cyclopentylbutyramide is distilled nol are treated with 224 parts of3-ethylcycloat about 188-19? 0. and 2 mm. pressure. It

pentanone and 60 parts of Raney nickel in alcohas the structural formulaholic suspension. This mixture is hydrogenated in a Parr bomb at 700lbs. pressure and 110-120 cum CH-CHz-CHrCHrC o-N-cuicnicuicmmouoi C. for8 hours. After cooling to room tempera- V A ture the contents of thebomb are filtered. and O (0 94 vacuum distilled. 268 parts of theresidue con- 15 V taining the N,N-diisopropyl-N'-(3-ethylcyclo- EXAMPLE5 pentyDputrescine are refluxed with 160 parts of Mmdiemmammoemm)3-methylcyclopentylacetyl chloride (cf. C. D. Nenitzescu et al., Ber.deut. chem. Ges. 71:2056; 1 3 in 3600 parts of benzene for 5 hours. The2a 183 f 0f vy l h wl utyryl qride are reaction mixture is extractedwith dilute hydroreacted Wlth 198 parts of N-dlethylammoethylchloricacid and the extract is made alkaline hexahydroamline in 2600 parts ofbenzene at with dilute alkali and extracted with ether. Thisatemperature for 4-5 hours. The reether extract is dried over anhydrouspotassium action mlxture is extracted wi i u hy rocarbonate, stirredwith charcoal and filtered. chloric d and e extract is made al aliecyclohezylbutyramide The filtrate, on evaporation yields, N,N-diisg-The base is extracted with ether and distilled propyl N (3 th l l t 3-at about 210-212 C. at 2 mm. pressure. The methylcyclopentylacetyl)putrescine which boils N t y a t yl N- cyclohexyl 'y 57 at about 215-225C. and about 1.5 mm. preshexylbutyramide is treated with alcoholichysur-e. The analysis as CH48N2O confirms the drogen chloride in dryether and upon chilling structure to be in the ice bath the crystallinehydrochloride is CHa-CHCH2 CH(CH3)2 CH-C H:'C 0-l 'TCHsC H2- oHi-cHi-NGER-C 2 /CH CH(CHa) CH2 CHa CHHCH-CzH I EXAMPLE 3 obtained which meltsat" about 123-125 C. It

N-(p-diethylaminoethyl)-N-cycZohe:cyZ-phas the Structural mmmlacyclohemyzpmpmmmzde (cum cH-om-om-cm-c o-N-cB=-cHi-1 (cd1.

A solution of 174 parts of ,B-cyclohexylpro- V A E pionyl chloride and198 parts of N -diethylamino- CH (cum i 1 ethylhexahydroaniline in 2600parts of benzene V is heated at reflux temperature for 4 hours. The E APLE 6 r ction mixture is extracted with dilute hydro- N (fidiemylammoethyl) N cyczohe:wlia

chloric acid, the extract is made alkaline and the base is extractedwith ether and distilled at cyczohexywazemmzde about 2034050 C at 2 mmpressure The 202 parts of a-cyclohexylvaleryl chloride areethylaminoefihy] N cyclohexyl B cyclghexylreacted with 198 parts ofN-diethylaminoethyl- .propionamide hydrochloride melts at abouthexahvdroaniline in 2600 parts of benzene atte- 7 1 9 C. uponrecrystallization fr m ethyl flux temperature for 4-5 hours withmechanical acetate, It ha th structural formula stirring. The resultingmixtureisextracted with A dilute hydrochloric acid and the extract ismade (CH2)5 (JH-CH -CH -CO-NCH -OH N(C H alkaline. The base is extractedwith ether and V A distilled at about 208-210 C. at 1.5 mm. prescn' oHmsure. 150 parts of the N-diethylaminoethyl-N- Km 50cyelohexyl-c-cyclohexylvaleramide are dissolved EXAMPLE 4 in dry etherand treated with alcoholic hydrogen chloride. Upon standing at 0 C. thehydrochloride precipitates, which melts at about 88-90 C. It has thestructural formula N- (a-dz'methylaminobutyl)-N-cycZopentyZ-vcyclopentylbutyramz'de A solution of 168 parts ofcyclopentanone in 200 parts of ethanol is treated with 232 parts (CH2);CH-(CH2)r-CO-N-CH2-CH2N(C2H5)2 of N,N-dimethylputrescine and 50 parts ofRaney V nickel and the mixture is hydrogenated in a CH (cum Parr mediumpressure bomb for 6 hours at V Hm 100-110 C. and about 650 lbs.pressure. After I claim:

cooling the contents of the bomb are filtered A compound 0f the u ur muand the filtrate is evaporated. The residue yieldsN,N-dimethyl-N'-cyclopentylputrescine upon distillation at about 96-104"0. and '7 mm. pressure. Y

A 80111111011 Of 134 parts of the i l ate a 5 wherein X and Y are lowercycloalkyl radicals, 174 p t of y l p ntylpropi nyl hl rid in A is alower alkylene radical and B is a lower alkylene radical separating the2 nitrogen atoms attached thereto by at least 2 carbon atoms.

2. An amide of the structural formula wherein n and m are integersgreater than 3 and smaller than 6 and B is a lower alkylene radicalseparating the 2 nitrogen atoms attached thereto by at least 2 carbonatoms.

3. An amide of the structural formula wherein B is a lower alkyleneradical separating the 2 nitrogen atoms attached thereto by at least 2carbon atoms.

4. N diethylaminoethyl-N-cyclohexyl a. cyclohexylacetamide.

5. An amide of the structural formula wherein n and m are integersgreater than 3 and smaller than 6 and B is a lower alkylene radicalseparating the 2 nitrogen atoms attached thereto by at least 2 carbonatoms.

6. An amide of the structural formula wherein B is a lower alkyleneradical separating the 2 nitrogen atoms attached thereto by at least 2carbon atoms.

7. N diethylaminoethyl N cyclohexyl-ficyclohexylpropionamide.

8. An amide oi the structural formula (CH2), CH-(CH2)a-C 0NBN(1oweralkyl);

A CH (CH2)...

wherein n and m are integers greater than 3 and smaller than 6 and B isa lower alkylene radical separating the 2 nitrogen atoms attachedthereto by at least 2 carbon atoms.

9. An amide of the structural formula A (0211 CH(CHa)s-C ONBN(loweralkyl);

CQCHD:

wherein B is a lower alkylene radical separating the 2 nitrogen atomsattached thereto by at least 2 carbon atoms.

10. N-diethylaminoethyl N cyclohexyl-vcyclohexylbutyramide.

11. the amides of the structural formula wherein n and m are integersgreater than 3 and smaller than 6 and B is a lower alkylene radicalseparating the 2 nitrogen atoms attached thereto by at least 2 carbonatoms.

12. The compounds of the structural formula wherein B is a loweralkylene radical separating the 2 nitrogen atoms attached thereto by atleast 2 carbon atoms.

13. N-diethylaminoethyl N cyclohexyl-6 cyclohexylvaleramide.

JOHN W. CUSIC.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Cheney at al.: J. Am. Chem. Soc, vol. 64 (1942), pp. 970-3.

Villani et al.: J. Am. Chem. Soc," vol. 72, June 1950, pp. 2724-7(received Oct. 7, 1949).

1. A COMPOUND OF THE STRUCTURAL FORMULA